Tinnitus is commonly referred to as ‘ringing in the ears’—the perception of sounds in the absence of an external source of acoustic signals. Tinnitus has been defined as “the perception of a sound which results exclusively from the activity within the nervous system without any corresponding mechanical, vibratory activity within the cochlea, that is, tinnitus as an auditory phantom perception” (Jastreboff et al., J Am Acad Audiol 2000; 11(3): 162-177). Tinnitus is frequently associated with a decreased sound tolerance (i.e. hyperacusis).
The pathophysiology of subjective tinnitus is poorly understood and a definitive pathogenesis of tinnitus is unknown. Many environmental and substance-induced factors may cause tinnitus. Among the most frequently cited factors are acute acoustic trauma, occupational noise, and recreational music. In general, tinnitus seems to be the result of neuronal dysfunction within the auditory pathway. This dysfunction is misleadingly perceived as sound by higher auditory centers and can lead to functional alterations within the auditory nervous system. Maladaptive functional changes in cortical structures could result in an altered balance between excitatory and inhibitory neurotransmission and may lead to more severe tinnitus. In all cases, a potential malfunction in auditory pathways and auditory cortex is related to the activity of the prefrontal cortex and limbic system.
In most cases (95%), the perceived tinnitus is purely subjective in nature, e.g. no physical source of acoustic signals can be identified and, therefore, cannot be heard externally. A physical examination is performed to exclude objective tinnitus, e.g. the patient's perception of sound is caused by a real source of sound waves, e.g. the sound from turbulent flow in blood vessels reaching the cochlea. Tinnitus may be classified according to duration of tinnitus and the degree of tinnitus expression (e.g. severity or annoyance of the tinnitus) (McCombe et al., Clin Otolaryngol 2001; 26(5): 388-393 and Davis et al., Epidemiology of Tinnitus. In: Tyler R, editor. Tinnitus Handbook. San Diego: Singular Publishing Group; 2000. p. 1-23). Regarding the impact of tinnitus, tinnitus may be severely annoying to the patient and may be accompanied by social and psychological complications.
It has also been suggested that tinnitus may be further classified into two groups, peripheral tinnitus and central tinnitus, based on differences in how the tinnitus is perceived by the affected individual. Peripheral (or cochlear) tinnitus is presumed to originate from the peripheral nervous system and cochlea, and central tinnitus is presumed to originate in the auditory cortex.
Cochlear physiology provides some understanding of the origins of that form of the disease associated with the cochlea. Two rows of hair cells are found in the cochlea. Outer hair cells (OHC) actively contract in the presence of sound, and thus augment incoming low-oscillation signals and modulate the response of inner hair cells (IHC). Exposure to noise, including constant, repeated or even one single “blast trauma”, can damage cochlear hair cells, especially their fragile stereocilia. Since the OHC require substantially more oxygen than the IHC, they are more sensitive to noise, ototoxic drugs, trauma, etc. Due to the loss of active amplification, damage to the OHC can result in reduction of the dynamic range of the auditory system and impaired frequency selectivity. Uncontrolled contraction of damaged OHC can lead to stimulation of IHC and to nerve action potentials that are interpreted as sounds by the brain. Damage to the IHC can lead to abnormal deflection of the stereocilia, causing the cells to depolarize, leading to uncontrolled release of neurotransmitters which, again, can cause the perception of sound without a real source (Baguley, Br Med Bull. 2002; 63:195-212).
With the passage of time, higher levels of the auditory pathway may be involved, and the perception of tinnitus may not depend on the cochlear pathology any longer. A massive central amplification takes place, triggered by pathological cognitive focussing. Presumably, amplifying feedback mechanisms between the limbic system and cognitive areas of the CNS are established (Zenner, Ziel. Dtsch Arztebl. 2001; 37:2361-2365).
While a large number of afferent, mainly glutamatergic nerve fibers originate at the IHC (Furness, et al., J Neurosci. 2003 Dec. 10; 23(36):11296-11304), the OHC are the target of efferent nerve fibers with acetylcholine being the principal efferent neurotransmitter in the cochlea (Dallos et al, J Neurosci. 1997 Mar. 15; 17(6):2212-2226). An excess of glutamate in cochlear neurons is believed to contribute to tinnitus. Therefore, several approaches to tinnitus treatment have been made by using NMDA receptor-blocking substances, such as acamprosate or caroverine. Studies with these substances have shown limited success, possibly because the treatment target was mainly the afferent part of the auditory system while efferent neurotransmission was only marginally influenced.
Maison et al (J Neurosci. 2002 Dec. 15; 22(24):10838-10846) also describe efferent protection from acoustic trauma by overexpression of the α9/α10 nicotinic acetylcholine receptor complex.
So far, however, there are no well-established, specific medical treatments for tinnitus that provide replicable reduction of tinnitus and annoyance due to tinnitus, in excess of placebo effects (Dobie, Laryngoscope 1999; 109(8): 1202-1211; Eggermont et al., Trends Neurosci 2004; 27(11): 676-682; and Patterson et al., Int Tinnitus J 2006; 12(2): 149-159). Thus, a need exists for pharmaceutical products which are effective in treating or preventing tinnitus.
1-Amino-alkylcyclohexanes such as neramexane (also known as 1-amino-1,3,3,5,5-pentamethylcyclohexane) have been found to be useful in the therapy of various diseases especially in certain neurological diseases, including Alzheimer's disease and neuropathic pain. 1-Amino-alkylcyclohexanes such as neramexane are disclosed in detail in U.S. Pat. Nos. 6,034,134 and 6,071,966, the subject matter of which patents is hereby incorporated by reference. It is believed that the therapeutic action of 1-amino-alkylcyclohexanes such as neramexane is related to the inhibition of the effects of excessive glutamate at the N-methyl-D-aspartate (NMDA) receptors of nerve cells, for which reason the compounds are also categorized as NMDA antagonists, or NMDA receptor antagonists. Neramexane has also been disclosed to exhibit activity as an α9/α10 nicotinic receptor antagonist (Plazas, et al., Eur J Pharmacol., 2007 Jul. 2; 566(1-3):11-19).
U.S. Pat. No. 6,034,134 discloses that 1-amino-alkylcyclohexanes may be useful in the treatment of tinnitus due to their activity as NMDA receptor antagonists.
The instant inventors have discovered that 1-amino-alkylcyclohexanes, such as neramexane, are effective in treating cochlear tinnitus.